Acute kidney injury (AKI) is a common complication among ambulatory and hospitalized patients, and its incidence has increased by 11% in recent years. It is a rapidly progressive illness that independently predicts excess morbidity and mortality. Twenty percent to 60% of patients with acute kidney injury require dialysis, and mortality rates range from 15% in the community setting to 50% to 80% in the setting of multiorgan failure to more than 80% in the postoperative setting. Less severe forms of acute kidney injury may also result in prolonged hospitalization. These characteristics contrast with those of other kidney diseases, such as chronic kidney disease, which is typified by an insidious decline in renal function and is usually nonprogressive during hospitalization. Acute kidney injury is also distinct from prerenal azotemia, a physiologic response of the kidney to various predisposing factors (volume depletion, diuretic use, renin-angiotensin blockade, congestive heart failure, or cirrosis of the liver) that promptly resolve on fluid administration, regimen modification, or amelioration of the non-kidney organ malfunction.
It is critical to distinguish acute kidney injury from prerenal azotemia and chronic kidney disease at the time of patient presentation to rapidly manage associated illness. However, the initial measurement of serum creatinine, the standard marker of kidney function, does not distinguish acute kidney injury from prerenal azotemia or chronic kidney disease. In addition, the initial measurement of serum creatinine cannot reflect the extent of injury because its accumulation always lags behind the insult. Even a large decline in glomerular filtration rate (GFR) may manifest as a small change in serum creatinine level, particularly in the initial 48 hours after acute kidney injury before steady-state equilibrium is reached. Serum creatinine may also vary by age, race, sex, muscle mass, metabolism, nutritional status, comorbid conditions, hydration status, and medication use and consequently may not increase in proportion to the severity of the injury. As a result, the diagnosis of acute kidney injury currently requires measuring serum creatinine repeatedly and delaying maneuvers to prevent ongoing kidney damage, such as stopping use of nonsteroidal anti-inflammatory drugs, adjusting medication dosages, or correcting hemodynamic status. Even elevations of serum creatinine level that do not meet established criteria for acute kidney injury are associated with excess mortality, prolonged hospitalization, functional decline, and elevated financial costs, which highlights the insensitivity of serum creatinine measurement as a diagnostic test. These limitations in the use of serum creatinine provide the rationale for the discovery of kidney proteins that are expressed at the onset of injury and are more sensitive and specific for the diagnosis of acute injury than current diagnostic tests.
Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2, siderocalin, and 24P3′, is secreted into the urine by the thick ascending limb of Henle and collecting ducts of the kidney (See Mishra J et al., J Am Soc Nephrol. 2003; 14:2534-43, and Schmidt-Ott K M, et al., J Am Soc Nephrol. 2007; 18:407-13, the disclosures of which are incorporated herein by reference. At these sites, NGAL is likely to play a critical role in host defense by chelating iron-siderophore complexes that enhance microbial growth or mediate oxidative damage. In some segments of the nephron, NGAL may also recycle the iron complexes by endocytosis. Urinary NGAL is expressed in proportion to the degree of acute injury, whereas in chronic kidney disease, urinary NGAL is expressed in patients with progressive but not stable kidney failure. Volume depletion or diuretics do not increase urinary NGAL levels in mice, again reflecting the specificity of NGAL for ongoing tubular damage. These observations suggest not only that urinary NGAL detects acute kidney injury but also that its degree of expression might distinguish among acute kidney injury, prerenal azotemia, and chronic kidney disease. In addition, because NGAL is detectable before the accumulation of serum creatinine, NGAL might be used to diagnose acute kidney injury at patient presentation even when changes in serum creatinine level are incipient.